Synthesis of homoaporphine-type alkaloids via intramolecular phenol alkylation, design and synthesis of a new class of Trypanosoma brucei growth inhibitors, and neurons that matter : using light to tag neuronal ensembles based on function

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2017-05-03

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Meis, Alan Ronald

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Abstract

The synthesis of a homoaporphine-type alkaloid was accomplished in 10-steps. The synthesis featured a synthetic strategy to establish the key quaternary center through an early Suzuki cross coupling and a late-stage p-phenolic C-alkylation reaction, which proceeded in high yields. A medicinal chemistry and rational drug design approach was undertaken to design and synthesize a new class of Trypanosoma brucei growth inhibitors. This hit-to-lead strategy resulted in compounds with up to a 25-fold increase in efficacy towards T. brucei growth inhibition, with respect to the initial hit compound, and a single compound with activity in sub-micromolar concentrations. A collaborative effort has begun to develop a function based method to label or tag neurons. We have developed a photocaged derivative of erythromycin A in order to control gene expression within neurons using light. The photochemical properties of the photocaged-erythromycin derivative were studied and in vitro proof of principle assays are currently underway.

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